权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Impact of locus coeruleus-derived tau pathology in a rodent model of early Alzheimer's disease

蓝斑源性 tau 蛋白病理学对早期阿尔茨海默病啮齿动物模型的影响

基本信息

批准号：
10579830
负责人：
Shella D Keilholz
金额：
$ 46.1万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579830
关键词：
Affect Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease therapy Amyloid Amyloid beta-Protein Animals Anti-Inflammatory Agents Anxiety Disorders Area Arousal Attention Behavior Behavioral Paradigm Brain Brain region Cell Nucleus Clinical Trials Cognition Cognitive Data Dementia Depressed mood Diagnostic Disease model Early treatment Elderly Electrophysiology (science)Faculty Functional Magnetic Resonance Imaging Functional disorder Goals Healthcare Systems Hippocampus Human Human Amyloid Precursor Protein Hyperactivity Impaired cognition Inflammation Intervention Learning Lesion Mediating Memory impairment Mental Depression Morphology Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Norepinephrine Pathogenicity Pathologic Pathology Patients Pattern Performance Phenotype Property Prosencephalon Psyche structure Quality of life Rat Transgene Rattus Research Research Personnel Rest Rodent Rodent Model Senile Plaques Severities Sleep Disorders Stimulus Symptoms Testing Therapeutic Time Transgenes Transgenic Mice Viral Viral Vector biological adaptation to stress cognitive process entorhinal cortex experimental study extracellular frontal lobe imaging study in vivo innovation interest locus ceruleus structure loved ones mutant neurobehavioral neuroinflammation neuron loss neuropathology neuroprotection neuropsychiatry neurotoxicity noradrenergic norepinephrine system novel novel therapeutic intervention optogenetics presenilin-1 prevent prodromal Alzheimer&apos s disease promoter stressor targeted treatment tau Proteins tau aggregation tau mutation therapeutic target tool transmission process

项目摘要

Amyloid-β (Aβ) plaques and tau neurofibrillary tangles, as well as neuronal death, are the pathologic hallmarks of Alzheimer's disease (AD). Therapeutic efforts focused on Aβ have thus far failed, underscoring the urgent need for alternate approaches, particularly those that can target early AD. Aberrant tau in the locus coeruleus (LC), the major noradrenergic nucleus in the brain that regulates attention, arousal, stress responses, and cognition, is the earliest detectable AD-like neuropathology in the human brain, and LC degeneration is ubiquitious in later AD. Recent research indicates that early LC dysfunction may contribute to prodromal AD symptoms such as depression, anxiety, and sleep disorders, while later LC degeneration exacerbates cognitive impairment. Although these data suggest that the LC is a promising therapeutic target in AD, almost nothing known about how pathogenic tau impacts LC function and survival. We have developed a viral vector that drives the expression of wild-type human tau exclusively in LC neurons, which over time becomes hyperphosphorylated and misfolded, thus recapitulating the earliest forms of human AD. We will use this novel tool to study the consequences tau pathology in the LC. In Aim 1, we will determine the impact of different forms of aberrant tau on LC neuron morphology, survival, and local inflammation, and assess the potential of LC-derived tau pathology to spread to interconnected forebrain regions. In Aim 2, we will use in vivo electrophysiology and behavioral paradigms to evaluate how tau pathology affects LC activity and performance in neuropsychiatric and cognitive domains. In Aim 3, we will combine optogenetics and fMRI to determine how aberrant tau influences LC-forebrain functional connectivity. Completion of these aims will lay the groundwork for LC/tau-based therapies for early AD.

β 淀粉样蛋白 (Aβ) 斑块和 tau 神经原纤维缠结以及神经元死亡是病理标志阿尔茨海默病（AD）。迄今为止，针对 Aβ 的治疗努力已经失败，这凸显了迫切需要解决的问题。需要替代方法，特别是那些可以针对早期 AD 的方法。蓝斑中的异常 tau 蛋白 (LC)，大脑中主要的去甲肾上腺素能核，调节注意力、唤醒、压力反应和认知，是人类大脑中最早可检测到的类似 AD 的神经病理学，而 LC 变性是在公元后期普遍存在。最近的研究表明早期 LC 功能障碍可能导致 AD 前驱期抑郁、焦虑和睡眠障碍等症状，而随后的 LC 变性会加剧认知能力损害。尽管这些数据表明 LC 是 AD 有希望的治疗靶点，但几乎没有什么了解致病性 tau 蛋白如何影响 LC 功能和存活。我们开发了一种病毒载体仅在 LC 神经元中驱动野生型人类 tau 蛋白的表达，随着时间的推移，过度磷酸化和错误折叠，从而重现了人类 AD 的最早形式。我们将使用这本小说研究 LC 中 tau 病理学后果的工具。在目标 1 中，我们将确定不同因素的影响异常 tau 蛋白的形式对 LC 神经元形态、存活和局部炎症的影响，并评估 LC 衍生的 tau 蛋白病理学扩散到相互连接的前脑区域。在目标 2 中，我们将使用 vivo 电生理学和行为范式评估 tau 病理学如何影响 LC 活性和性能在神经精神学和认知领域。在目标 3 中，我们将结合光遗传学和功能磁共振成像来确定如何异常的 tau 蛋白会影响 LC-前脑的功能连接。完成这些目标将为我们奠定基础用于早期 AD 的 LC/tau 疗法。